Serial analysis of gene expression of lobular carcinoma in situ identifies down regulation of claudin 4 and overexpression of matrix metalloproteinase 9.
BACKGROUND
Although lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Global gene expression profiling of LCIS has not been performed.


METHODS
We analysed the comprehensive gene expression profile of a unique case of mass-forming LCIS using serial analysis of gene expression (SAGE). This SAGE library is publicly available online. By comparing the gene expression profile of LCIS to that of benign breast epithelium and stroma, we identified several genes up and down regulated in LCIS. Differential expression of selected genes not previously studied in LCIS was validated at the protein level by immunohistochemistry and at the RNA level by quantitative reverse transcriptase PCR (RT-PCR).


RESULTS
We identified down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 in LCIS relative to normal breast epithelium and stroma. We validated these findings by immunohistochemistry in a separate series of 11 and 19 LCIS cases, respectively. Overexpression of matrix metalloproteinase 9 was further confirmed by quantitative RT-PCR analysis of the index case.


CONCLUSIONS
We have created the first global gene expression profile of LCIS, and demonstrated down regulation of cell junction proteins (an expected result) and overexpression of matrix metalloproteinase 9 (an unexpected result). Additional analysis of this data made available as an online resource should facilitate further molecular characterisation of LCIS.
Cao
Dengfeng
D
Departments of Pathology and Immunology, Washington University, St Louis, MO, USA.
Polyak
Kornelia
K
Halushka
Marc K
MK
Nassar
Hind
H
Kouprina
Nina
N
Iacobuzio-Donahue
Christine
C
Wu
Xinyan
X
Sukumar
Saraswati
S
Hicks
Jessica
J
De Marzo
Angelo
A
Argani
Pedram
P
D000328:Adult; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism; D062506:Claudin-4; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C568157:CLDN4 protein, human; D062506:Claudin-4; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020780:Matrix Metalloproteinase 9